The present invention relates to a series of thianaphthene derivatives which have been found to have certain valuable therapeutic activities. The invention also provides processes for preparing these compounds and methods of using them.
The compounds of the invention have the ability to inhibit blood platelet aggregation and to inhibit the biosynthesis of thromboxane A.sub.2 (hereinafter referred to, as is conventional, as "TXA.sub.2 ").
The compounds of the present invention may be regarded as derivatives of thianaphthene ["The Merck Index", Tenth Edition (1983) monograph 9142], which has the formula (A): ##STR2## In accordance with the recommendations of the International Union of Pure and Applied Chemistry, Commission of Nomenclature of Organic Chemistry, the compounds of the present invention are named semi-systematically, taking thianaphthene as the parent compound. For the avoidance of doubt, the numbering system employed herein is that shown on the above formula (A).
TXA.sub.2 plays an important role in inducing blood platelet aggregation, and inhibiting its biosynthesis is believed to reduce the extent of blood platelet aggregation, apart from any direct effect the compounds may have on such aggregation. It is known that TXA.sub.2 is produced from prostaglandin endoperoxide PGH.sub.2 via PGG.sub.2. It is known that the activity of TXA.sub.2 is generally opposite to that of PGI.sub.2, which causes vasodilation and prevents platelet aggregation. Accordingly, it has been suggested that the balance within the blood between TXA.sub.2 and PGI.sub.2 is a controlling factor in the development and/or cure of thrombosis. Accordingly, it is desirable for the treatment or propyhylaxis of thromboembolisms to inhibit selectively the biosynthesis of TXA.sub.2 and thereby to enhance the activity of PGI.sub.2 (which has an inhibitory effect on platelet aggregation) and also to increase the level of PGI.sub.2 as a result of accumulation of PGH.sub.2.
It is believed that an effective inhibitor of the biosynthesis of TXA.sub.2 would be of considerable value in the treatment or propyhylaxis of a variety of diseases and disorders associated with the circulatory system. It is, however, important that this inhibitory activity should not be accompanied by inhibition of the enzymes responsible for the synthesis of other prostaglandins.
Various compounds have been proposed for such use. A proposal has been made to use certain thianaphthene derivatives for this purpose and those compounds disclosed in European Patent Specification No. and the corresponding U.S. Pat. No. 4,496,752 do exhibit the necessary activity.
We have now discovered that certain thianaphthenes in which the 6-membered ring is partially saturated have an outstanding ability to inhibit TXA.sub.2 synthesis which is an order of magnitude or more better than that of known compounds which are currently available for this purpose. Although superficially similar to the compounds of the invention, the compounds of EP 73663B1 have a fully unsaturated and aromatized thianaphthene ring system. On the contrary, the compounds of the invention have a partially saturated 6-membered ring. The aromaticity of the prior compounds leads to a rigidity of molecular structure and configuration and a fluidity of electron flow which are not possessed by the compounds of the present invention and which would be expected to have a major influence on the biological properties of the compounds. It is, therefore, surprising that the compounds of the invention possesses biological properties similar in nature to those of the prior compounds, especially since the activity concerned relates to the inhibition of enzymes, where it would be expected that the differences between the prior compounds and the compounds of the invention would have a substantial influence.